169 research outputs found
Formation of Supermassive Black Holes
Evidence shows that massive black holes reside in most local galaxies.
Studies have also established a number of relations between the MBH mass and
properties of the host galaxy such as bulge mass and velocity dispersion. These
results suggest that central MBHs, while much less massive than the host (~
0.1%), are linked to the evolution of galactic structure. In hierarchical
cosmologies, a single big galaxy today can be traced back to the stage when it
was split up in hundreds of smaller components. Did MBH seeds form with the
same efficiency in small proto-galaxies, or did their formation had to await
the buildup of substantial galaxies with deeper potential wells? I briefly
review here some of the physical processes that are conducive to the evolution
of the massive black hole population. I will discuss black hole formation
processes for `seed' black holes that are likely to place at early cosmic
epochs, and possible observational tests of these scenarios.Comment: To appear in The Astronomy and Astrophysics Review. The final
publication is available at http://www.springerlink.co
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms
Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline
The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline
Bifunctional Avidin with Covalently Modifiable Ligand Binding Site
The extensive use of avidin and streptavidin in life sciences originates from the extraordinary tight biotin-binding affinity of these tetrameric proteins. Numerous studies have been performed to modify the biotin-binding affinity of (strept)avidin to improve the existing applications. Even so, (strept)avidin greatly favours its natural ligand, biotin. Here we engineered the biotin-binding pocket of avidin with a single point mutation S16C and thus introduced a chemically active thiol group, which could be covalently coupled with thiol-reactive molecules. This approach was applied to the previously reported bivalent dual chain avidin by modifying one binding site while preserving the other one intact. Maleimide was then coupled to the modified binding site resulting in a decrease in biotin affinity. Furthermore, we showed that this thiol could be covalently coupled to other maleimide derivatives, for instance fluorescent labels, allowing intratetrameric FRET. The bifunctional avidins described here provide improved and novel tools for applications such as the biofunctionalization of surfaces
A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome
Glutathione pathway gene variation and risk of autism spectrum disorders
Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case–parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary
Airway and Esophageal Stenting in Patients with Advanced Esophageal Cancer and Pulmonary Involvement
BACKGROUND: Most inoperable patients with esophageal-advanced cancer (EGC) have a poor prognosis. Esophageal stenting, as part of a palliative therapy management has dramatically improved the quality of live of EGC patients. Airway stenting is generally proposed in case of esophageal stent complication, with a high failure rate. The study was conducted to assess the efficacy and safety of scheduled and non-scheduled airway stenting in case of indicated esophageal stenting for EGC. METHODS AND FINDINGS: The study is an observational study conducted in pulmonary and gastroenterology endoscopy units. Consecutive patients with EGC were referred to endoscopy units. We analyzed the outcome of airway stenting in patients with esophageal stent indication admitted in emergency or with a scheduled intervention. Forty-four patients (58+/-\-8 years of age) with esophageal stenting indication were investigated. Seven patients (group 1) were admitted in emergency due to esophageal stent complication in the airway (4 fistulas, 3 cases with malignant infiltration and compression). Airway stenting failed for 5 patients. Thirty-seven remaining patients had a scheduled stenting procedure (group 2): stent was inserted for 13 patients with tracheal or bronchial malignant infiltration, 12 patients with fistulas, and 12 patients with airway extrinsic compression (preventive indication). Stenting the airway was well tolerated. Life-threatening complications were related to group 1. Overall mean survival was 26+/-10 weeks and was significantly shorter in group 1 (6+/-7.6 weeks) than in group 2 (28+/-11 weeks), p<0.001). Scheduled double stenting significantly improved symptoms (95% at day 7) with a low complication rate (13%), and achieved a specific cancer treatment (84%) in most cases. CONCLUSION: Stenting the airway should always be considered in case of esophageal stent indication. A multidisciplinary approach with initial airway evaluation improved prognosis and decreased airways complications related to esophageal stent. Emergency procedures were rarely efficient in our experience
Long-term social skills group training for children and adolescents with autism spectrum disorder: a randomized controlled trial
Social skills group training (SSGT) is widely used for intellectually able children and adolescents with autism spectrum disorder (ASD). Previous studies indicate small to moderate effects on social communication capacities. The duration of most available programs is relatively short, and extended training might lead to further improvement. This randomized controlled trial compared an extended 24-week version of the SSGT program KONTAKT with standard care. The weekly sessions gradually shifted in content from acquisition of new skills to real-world application of the acquired skills. A total of 50 participants with ASD (15 females; 35 males) aged 8–17 years were included. The study was conducted at two child and adolescent psychiatry outpatient units in Sweden. The primary outcome was the Social Responsiveness Scale–Second Edition (SRS-2) rated by parents and blinded teachers. Secondary outcomes included parent- and teacher-rated adaptive behaviors, trainer-rated global functioning and clinical severity, and self-reported child and caregiver stress. Assessments were made at baseline, posttreatment, and at 3-months follow-up. Parent-rated SRS-2 scores indicated large effects posttreatment [- 19.2; 95% CI - 29.9 to - 8.5; p < .001, effect size (ES) = 0.76], which were maintained at follow-up (- 20.7; 95% CI - 31.7 to - 9.7; p < .0001, ES = 0.82). These estimates indicate substantially larger improvement than previously reported for shorter SSGT. However, the effects on teacher-rated SRS-2 and most secondary outcomes did not reach statistical significance. Our results suggest added benefits of extended SSGT training, implying that service providers might reach better results by optimizing the delivery of SSGT
Potentiation of Epithelial Innate Host Responses by Intercellular Communication
The epithelium efficiently attracts immune cells upon infection despite the low number of pathogenic microbes and moderate levels of secreted chemokines per cell. Here we examined whether horizontal intercellular communication between cells may contribute to a coordinated response of the epithelium. Listeria monocytogenes infection, transfection, and microinjection of individual cells within a polarized intestinal epithelial cell layer were performed and activation was determined at the single cell level by fluorescence microscopy and flow cytometry. Surprisingly, chemokine production after L. monocytogenes infection was primarily observed in non-infected epithelial cells despite invasion-dependent cell activation. Whereas horizontal communication was independent of gap junction formation, cytokine secretion, ion fluxes, or nitric oxide synthesis, NADPH oxidase (Nox) 4-dependent oxygen radical formation was required and sufficient to induce indirect epithelial cell activation. This is the first report to describe epithelial cell-cell communication in response to innate immune activation. Epithelial communication facilitates a coordinated infectious host defence at the very early stage of microbial infection
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